EP0367036B1 - Substituted 3-aminosydnonimines, process for their preparation and their use - Google Patents

Abstract

Substituted 3-aminosydnonimines of the formula I <IMAGE> (I) and their pharmacologically acceptable acid addition salts, wherein R1 denotes, for example, alkyl having 1 to 8 C atoms, R2 denotes hydrogen or the radical -COR3 and R3 denotes, for example, an aliphatic radical having 1 to 4 C atoms, are prepared, for example, by cyclization of a compound of the formula II <IMAGE> (II) and if appropriate subsequent acylation and have useful pharmacological properties.

Description

The invention relates inter alia to pharmacologically active substituted 3-aminosydnonimines.

US-A-3312690 discloses sydnonimines which carry a disubstituted amino radical in the 3-position and which have an antihypertensive effect. These 5-position Sydnonimines have a free imino group.

U.S.-A-3769283 discloses sydnonimines which carry a disubstituted amino residue in the 3-position and have hypotensive effects. The imino group in the 5-position is marked with -NO or e.g. substituted with alkylcarbonyl.

EP-A-0346684, which falls under Article 54 (3) EPC, relates to substituted 3-aminosydnomines with an effect on the cardiovascular system in which the 3-position amino group is replaced by a tert-butyl radical and the radical A- (CH ₂ ) _n - is disubstituted, where n is the number 2 or 3 and A is, for example, hydroxyl, alkoxy with 1 to 4 carbon atoms or dialkylamino with a total of 2 to 8 carbon atoms.

The prior art contains no evidence that sydnonimine derivatives with a monosubstituted amino radical in the 3-position have pharmacological properties or that from sydnonimines which have a disubstituted amino radical in the 3-position, in which one substituent is a tert-butyl radical, the tert .-Butyl residue can be split off.

und ihre pharmakologisch annehmbaren .Säureadditionssalze, worin

• R¹ Alkyl mit 1 bis 8 C-Atomen, Cycloalkyl mit 5 bis 8 C-Atomen, wobei der Alkyl- oder Cycloalkylrest auch mit -OR⁴ oder -N(R⁵, R⁶) substituiert sein kann, oder Adamantyl,
• R² Wasserstoff, -NO oder den Rest -COR³,
• R³ einen aliphatischen Rest mit 1 bis 6 C-Atomen, der auch mit Alkoxy mit 1 bis 6 C-Atomen oder mit einem Alkylthiorest mit 1 bis 4 C-Atomen oder mit Allylthio substituiert sein kann; einen cycloaliphatischen Rest mit 5 bis 7 C-Atomen; einen bicycloaliphatischen Rest mit 7 bis 14 C-Atomen; einen tricycloaliphatischen Rest mit 7 bis 16 C-Atomen; einen Alkoxyrest mit 1 bis 6 C-Atomen, der auch mit Alkoxy mit 1 bis 6 C-Atomen substituiert sein kann; einen Aryloxyrest mit 6 bis 10 C-Atomen; einen Alkoxycarbonylrest mit insgesamt 2 bis 7 C-Atomen; einen Arylrest mit 6 bis 10 C-Atomen; einen mit 1 bis 3 Halogenatomen und/oder 1 bis 3 Alkylresten mit 1 bis 3 C-Atomen und/oder 1 bis 3 Alkoxyresten mit 1 bis 3 C-Atomen und/oder 1 oder 2 Nitrogruppen und/oder 1 oder 2 Hydroxygruppen und/oder 1 oder 2 Alkylcarbonyloxyresten mit 1 bis 4 C-Atomen im Alkylteil mono-, di- oder trisubstituierten Arylrest mit 6 bis 10 C-Atomen; Imidazolyl, R⁴, R⁵, R⁶ Wasserstoff oder Alkyl mit 1 bis 6 C-Atomen bedeuten.

The invention now relates to pharmacologically active substituted 3-aminosydnonimines of the general formula I.

and their pharmacologically acceptable acid addition salts, wherein

• R ^{1 is} alkyl with 1 to 8 C atoms, cycloalkyl with 5 to 8 C atoms, where the alkyl or cycloalkyl radical can also be substituted with -OR ⁴ or -N (R ⁵ , R ⁶ ), or adamantyl,
• R ^{2 is} hydrogen, -NO or the radical -COR ³ ,
• R ^{3 is} an aliphatic radical with 1 to 6 C atoms, which can also be substituted with alkoxy with 1 to 6 C atoms or with an alkylthio radical with 1 to 4 C atoms or with allylthio; a cycloaliphatic radical with 5 to 7 carbon atoms; a bicycloaliphatic radical with 7 to 14 C atoms; a tricycloaliphatic radical with 7 to 16 carbon atoms; an alkoxy radical with 1 to 6 carbon atoms, which can also be substituted with alkoxy with 1 to 6 carbon atoms; an aryloxy radical having 6 to 10 carbon atoms; an alkoxycarbonyl radical with a total of 2 to 7 carbon atoms; an aryl radical with 6 to 10 carbon atoms; one with 1 to 3 halogen atoms and / or 1 to 3 alkyl radicals with 1 to 3 C atoms and / or 1 to 3 alkoxy radicals with 1 to 3 C atoms and / or 1 or 2 nitro groups and / or 1 or 2 hydroxy groups and / or 1 or 2 alkylcarbonyloxy radicals with 1 to 4 carbon atoms in the alkyl part of mono-, di- or tri-substituted aryl radicals with 6 to 10 carbon atoms; Imidazolyl, R ⁴ , R ⁵ , R ^{6 are} hydrogen or alkyl having 1 to 6 carbon atoms.

The invention further relates to a process for the preparation of the compounds according to the invention and their use, and to part of the starting products required for the preparation of the compounds according to the invention.

Aliphatic residues, alkyl residues, alkoxy residues, alkylamino residues and dialkylamino residues can be straight-chain or branched. This also applies if they appear as substituents on other residues.

The alkyl radicals representing R ⁵ and R ⁶ can be the same or different.

Examples of R ¹ are: methyl, ethyl, n-propyl, i-propyl, n-, i-, sec- and tert-butyl, n-, i-pentyl, n-, i-hexyl, n-, i-heptyl, n-, i-octyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-hydroxyethyl, 2- or 3-hydroxypropyl, 2-, 3- or 4-hydroxybutyl, 3-, 4- or 5-hydroxy-2 -methyl-pentyl, 2-methoxy-, -ethoxy-, -propoxy-ethyl, 3-methoxy-, -ethoxy-, -propoxy-propyl, 3-isopropoxy-propyl, 4-butoxy-butyl, 2-amino-, -Dimethylamino-, - Diethylamino-, -Methylethylamino-, -Methylpropylamino-ethyl, 4-Dibutylamino-butyl, 2- or 3-Hydroxycyclopentyl, 2-, 3- or 4-Hydroxycyclohexyl, 2-, 3- oder 4- Hydroxycycloheptyl, 2-, 3-, 4- or 5-hydroxycyclooctyl, 2-, .3- or 4-methoxy-, -ethoxy-, -propoxy-, -butoxy-cyclohexyl, 2-, 3- or 4-amino- , -Dimethylamino-, - Diethylamino-, -Methylethylamino-cyclohexyl, 1-Adamantyl.

For R ¹ , preference is given to: alkyl having 1 to 6 carbon atoms, furthermore hydroxyalkyl having 2 to 6 carbon atoms, cyclohexyl and hydroxycyclohexyl, in particular 2-hydroxycyclohexyl, adamantyl.

Particularly preferred radicals for R ¹ are: methyl, ethyl, i-propyl, neopentyl, cyclohexyl, 2-hydroxyethyl, adamantyl, 2-hydroxycyclohexyl, of which ethyl, i-propyl, cyclohexyl, 2-hydroxycyclohexyl and 1-adamantyl are very particularly preferred are. 2nd

For R ² are preferred: hydrogen, acetyl, propionyl, i-propylcarbonyl, tert-butylcarbonyl, cyclohexylcarbonyl, benzoyl, 4-chloroenzoyl, methoxycarbonyl, ethoxycarbonyl, i-propoxycarbonyl, butoxycarbonyl, allylthiomethylcarbonyl.

Suitable aliphatic radicals for R ³ are, in particular, alkyl radicals, preferably having 1 to 4 carbon atoms. The aliphatic radicals, in particular alkyl radicals, which represent R ³ can also be substituted with alkoxy having 1 to 6 C atoms, in particular 1 to 4 C atoms, preferably 1 to 3 C atoms. Examples of alkyl and alkoxyalkyl radicals which can represent R ³ are: methyl; Ethyl; n-propyl; i-propyl; n-, i-, sec.- and tert.-butyl; n- and i-pentyl; n- and i-hexyl; Methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxymethyl; 2-methoxy, 2-ethoxy, 2-n-propoxy, 2-i-propoxy, 2-n-butoxy-ethyl; 2-methoxy, 3-ethoxy, 3-n-propoxy, 3-i-propoxypropyl or -i-propyl. The aliphastic radicals which represent R ³ , in particular the alkyl radicals, can also be substituted by an alkylthio radical having 1 to 4 carbon atoms or preferably by allylthio (CH ₂ = CH-CH ₂ -S). Alkylthio radicals with 1 to 4 carbon atoms are, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl-thio. Suitable cycloaliphatic radicals for R ³ are, in particular, cycloalkyl radicals having 5 to 7 carbon atoms, in particular cyclopentyl, and preferably cyclohexyl. 2,6,6-Trimethylbicyclo (3.1.1) heptan-3-yl (= pinanyl-3) is particularly suitable as the bicycloaliphatic radical for R ³ . As for R ³ stehendertricycloaliphatischer rest comes particular tricyclo (3.3.1.1 ^{3. 7)} viewed decan-1-yl (= adamantyl) in.

The alkoxy radicals which stand for R ³ have in particular 1 to 4 C atoms, preferably or 2 C atoms. The alkoxy substituents for the alkoxy radicals have in particular 1 to 4 carbon atoms. Examples of alkoxy radicals and alkoxyalkoxy radicals which can stand for R ³ are: methoxy; Ethoxy; n- and i-propoxy; n-, i-, sec.- and tert.-butoxy; n-pentoxy; i-hexoxy; Methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy-methoxy; 2-methoxy, 2-ethoxy, 2-n-propoxy, 2-i-propoxy-ethoxy; 3-methoxy, 3-ethoxy, 3-n-propoxy, 3-i-propoxypropoxy; 4-methoxy, 4-ethoxy, 4-n-propoxy, 3-propoxy, 4-n-butoxy-butoxy.

The alkoxycarbonyl radical representing R ³ preferably has 2 to 5 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy-carbonyl. As the alkoxycarbonyl radical for R ³ , the ethoxycarbonyl radical is particularly suitable.

Examples of aryl radicals which stand for R ³ are a- or β-naphthyl radicals, but in particular the phenyl radical. Examples of aryloxy radicals which stand for R ³ are a- or β-naphthoxy radicals, but in particular the phenoxy radical. The aryl radicals which stand for R ³ can be mono-, di- or tri-substituted, but only a maximum of 2 nitro groups, such as 2-methyl-4,6-dinitrophenyl and 2-chloro-6-, can be present even when trisubstituted. methyl-4-nitrophenyl. Halogen substituents for the aryl radicals are, for example, fluorine, chlorine and / or bromine atoms. Examples of alkylcarbonyloxy substituents for the aryl radicals, in particular for a phenyl radical, are: acetoxy, n-propionyloxy, i-propionyloxy, n-butyryloxy, i-butyryloxy.

Examples of the optionally substituted aryl radicals representing R ³ are: phenyl, 2-,, 3- or 4-methyl-, -ethyl-, -n-propyl-, -i-propyl-phenyl; 2-, 3- or 4-methoxy-, -ethoxy-, -n-propoxy-, -i-propoxyphenyl; 2-, 3- or 4-fluoro, chloro or bromophenyl; 2-, 3- or 4-nitrophenyl; 2-, 3- or 4-hydroxyphenyl; 2-, 3- or 4-acetoxy-, -n-propionyloxy-, -n-butyryloxyphenyl; 2,3-, 2,4-, 2,5- or 2,6-dimethyl-, -diethyl-, -dipropyl-phenyl; 2- or 3-methyl-4-chlorophenyl; 2- or 3-ethyl-4-fluorophenyl; 2-chloro-4-ethylphenyl; 2-bromo-4-i-propylphenyl; 2,6-diethoxy-4-chlorophenyl; 2,3,4-, 3,4,5- or 2,3,5-trimethyl, triethyl, tripropyl, trimethoxy, triethoxy or tripropoxyphenyl; 2-hydroxy-3-, -4- or -5-chlorophenyl; 2-methyl-3-, -4- or -5-acetoxyphenyl.

The substituted aryl radicals which stand for R ³ are in particular to be mentioned: methylphenyl (= tolyl), nitrophenyl and chlorophenyl. The imidazolyl radical representing R ³ is preferably a 1-imidazolyl radical.

For R ³ are preferred: methyl, ethyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-nitrophenyl, methoxy, ethoxy, n-propoxy, i-propoxy, 2-n-propoxy-ethoxy, 2-i-propoxy-ethoxy, n-butoxymethyl, 2-n-butoxy-ethoxy and allylthiomethyl.

R ⁴ is preferably hydrogen. The alkyl radicals representing R ⁴ , R ⁵ and R ⁶ preferably have 1 to 4 carbon atoms.

• a) eine Verbindung der allgemeinen Formel II
  
  worin R¹ die bereits genannte Bedeutung besitzt, zu einer Verbindung der allgemeinen Formel la
  
  cyclisiert wird und daß diese oder ein Säureadditionssalz davon für den Fall, daß eine Verbindung der Formel mit R² = -COR³ hergestellt werden soll, mit einem Acylierungsmittel, das den Rest -COR³ einführt, acyliert wird oder für den Fall, daß eine Verbindung der Formel I mit R² =-NO hergestellt werden soll, nitrosiert wird und die so erhaltene Verbindung gegebenenfalls in ein pharmakologisch annehmbares Säureadditionssalz überführt wird, oder daß
• b) aus einem 3-Aminosydnonimin der Formel 111
  
  worin R¹ und R² die bereits genannten Bedeutungen besitzen, das auch in Form eines Säureadditionssalzes vorliegen kann, der tert.-Butylrest abgespalten und durch Wasserstoff ersetzt wird, wobei normalerweise zunächst eine Verbindung der Formel la entsteht, die - für den Fall, daß eine Verbindung der Formel I mit R² = -COR³ hergestellt werden soll, wie vorstehend unter a) angegeben, direkt oder in Form eines Säureadditionssalzes mit einem Acylierungsmittel, das den Rest -COR³ einführt, acyliert wird oder für den Fall, daß eine Verbindung der Formel I mit R² =-NO hergestellt werden soll, nitrosiertwird und die so erhaltene Verbindung gegebenenfalls in ein pharmakologisch annehmbares Säureadditionssalz überführt wird.

A compound of formula 1 can be prepared in that

• a) a compound of general formula II
  
  wherein R ^{1 has} the meaning already mentioned, to a compound of general formula la
  
  is cyclized and that this or an acid addition salt thereof, in the event that a compound of the formula with R ² = -COR ^{3 is to be} prepared, is acylated with an acylating agent which introduces the radical -COR ³ , or in the event that one Compound of formula I with R ² = -NO is to be prepared, is nitrosed and the compound thus obtained is optionally converted into a pharmacologically acceptable acid addition salt, or that
• b) from a 3-aminosydnonimine of the formula 111
  
  in which R ¹ and R ^{2 have} the meanings already mentioned, which can also be in the form of an acid addition salt, the tert-butyl radical is cleaved and replaced by hydrogen, a compound of the formula Ia usually initially being formed which, in the event that a compound of formula I with R ² = -COR ³ is to be produced, as indicated above under a), directly or in the form of an acid addition salt with an acylating agent which introduces the radical -COR ³ , is acylated or in the event that one Compound of formula I with R ² = -NO is to be prepared, is nitrosated and the compound thus obtained is optionally converted into a pharmacologically acceptable acid addition salt.

The preparation of the compounds of the formula according to the invention in process variant b) is preferred.

The cyclization of compound II to compound la is carried out in a suitable organic or inorganic solvent, dispersant or diluent with the addition of a cyclizing agent, normally at temperatures from -10 to 40 ° C., in particular 0 to 40 ° C., preferably at 0 to 20 ° C.

Suitable cyclizing agents are those which set a pH of 3 or less in aqueous solution, e.g. strong acids, such as mineral acids, such as sulfuric, nitric or phosphoric acid, preferably hydrogen chloride, but also strong organic acids, such as trifluoroacetic acid. The cyclization is usually carried out under ice cooling. The cyclizing agent comes e.g. based on 1 mol of the compound of the formula II 0.1 to 10 mol, preferably 1 to 5 mol, for use. The cyclizing agent is normally used in excess. It is particularly convenient to use hydrogen chloride as the cyclizing agent, which is normally introduced into the reaction mixture until it is saturated. In the cyclization, the corresponding acid addition salt of compound la is normally obtained.

Suitable solvents, dispersants or diluents are, for example: alcohols, for example those with 1 to 8 C atoms, in particular those with 1 to 6 C atoms, preferably those with 1 to 4 C atoms, such as methanol, ethanol, i - and n-propanol, i-, sec- and tert-butanol, n-, i-, sec.-, tert.-pentanol, n-hexanol, 2-ethylbutanol, 2-ethylhexanol, isooctyl alcohol, cyclopentanol, cyclohexanol, methylcyclohexanol (Mixture), benzyl alcohol; Ethers, in particular those with 2 to 8 carbon atoms in the molecule, such as diethyl ether, methyl ethyl ether, di-n-propyl ether, di-isopropyl ether, methyl n-butyl ether, methyl tert-butyl ether, ethyl propyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, bis-β-methoxyethyl ether; Oligoethylene glycol dimethyl ether, such as tetraglyme or pentaglyme; Carboxylic acid alkyl esters, in particular those with 2 to 10 carbon atoms in the molecule, such as, for example, methyl, ethyl, butyl or isobutyl formate, methyl, ethyl, propyl, propyl, isopropyl or butyl acetate -, -isobutyl- or -sec-butyl-, -amyl-, -isoamyl-, -hexyl-, -cyclohexyl- or -benzyl-esters, propionic acid-methyl-, -ethyl- or -butyl-esters; Ketones, especially those with 3 to 10 carbon atoms in the molecule, such as acetone, methyl ethyl ketone, methyl n-propyl ketone, diethyl ketone, 2-hexanone, 3-hexanone, di-n-propyl ketone, di-iso-propyl ketone, di- iso-butyl ketone, cyclopentanone, cyclohexanone, methylcyclohexanone, dimethylcyclohexanone, benzophenone, acetophenone; aliphatic hydrocarbons such as hexane, heptane, low and high boiling petroleum ether, special gasoline and white spirit; cycloaliphatic hydrocarbons, such as cyclopentane, cyclohexane, methylcyclohexane, tetralin, Decalin; aromatic hydrocarbons, such as benzene, toluene, o-, m- and p-xylene, ethylbenzene; halogenated aliphatic or aromatic hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene; Hexamethylphosphoric triamide; Sulfoxides such as dimethyl sulfoxide; Tetramethylene sulfone; Water. Mixtures of various solvents or dispersants can also be used, for example water-methanol or preferably ethyl acetate-methanol.

The compounds of the formula Ia are compounds of the general formula according to the invention for the case where R ² = hydrogen.

worin X ein nukleophil abspaltbarer Rest darstellt.The acylation of the compound of formula la, which may also be in the form of an acid addition salt, to introduce the radical R ² = -COR ³ can be carried out in a manner known per se with a suitable acylating agent of formula IV

where X represents a nucleophilically cleavable radical.

In the formula IV, X is, for example, in particular halogen, preferably -CI or -Br; -OH; -O-alkyl, in particular with 1 to 5 carbon atoms; -O-aryl, the aryl radical being in particular a phenyl radical which can also be mono- or polysubstituted by alkyl, in particular methyl and / or nitro and is, for example, a tolyl, dinitrophenyl or nitrophenyl radical; -O-CO-R ³ ; -O-CO-O-alkyl, in particular with 1 to 5 carbon atoms in the alkyl radical, or the radical of an azole or benzazole bonded via an N atom with at least 2 N atoms in the quasi-aromatic five-membered ring.

The acylation is advantageously carried out in the liquid phase in the presence of an inert solvent, dispersant or diluent or in an excess of the acylating agent, advantageously with stirring.

In the case of acylation, the molar ratio between the compound of formula I and the acylating agent of the formula IV is theoretically 1: 1. The acylating agent of the formula IV is expediently used in a small molar excess. Excesses of up to 30 mol% are usually sufficient, i.e. the molar ratio between the compound of the formula Ia and the acylating agent of the formula IV is normally 1: (1 to 1.3), preferably 1: (1 to 1.2). If an acid is split off in the acylation reaction, the addition of an acid scavenger, e.g. an alkyl hydroxide, e.g. Sodium, potassium or lithium hydroxide, a tertiary organic amine such as e.g. Pyridine or triethylamine, an alkali carbonate or alkali bicarbonate, e.g. Soda or sodium bicarbonate, or an alkali salt of a weak organic acid, e.g. Sodium acetate., Useful. Suitable catalysts, such as e.g. 4-dimethylaminopyridine can be added.

In principle, the acylation can take place at temperatures between -10 ° C. and the boiling point of the solvent, dispersant or diluent used. In many cases the reaction is carried out at 0 to 50 ° C, in particular at 0 to 30 ° C and preferably at room temperature.

The compounds of formula IV are acylating agents and thus represent, for example: for X = halogen, acid halides or halogen formate esters, of which acid chlorides and chloroformate esters are preferred; for -OH carboxylic acids; for -O-alkyl and -O-aryl esters, of which the tolyl, 2,4-dinitro or 4-nitrophenyl esters are preferred; for -O-CO-R ³ anhydrides; for -O-CO-O-alkyl mixed carboxylic acid carbonic anhydrides; or heterocyclic amides or azolides, especially of N, N'-carbonyldiazoles, such as N, N'-carbonyldiimidazole, 2,2'-carbonylditriazole (1,2,3), 1,1'-carbonylditriazole (1 , 2,4), N, N'-carbonyl-dipyrazole, 2,2'-carbonyl-ditriazole (see e.g. HA Staab, M. Lücking and FH Dürr, Chem. Ber. 95, (1962), 1275 ff, HA Staab and A. Mannschreck, Chem. Ber. 95, (1962), 1284 ff .; HA Staab and W. Rohr, "Syntheses with Heterocyclic Amides (Azolides)" in "Newer Methods of Preparative Organic Chemistry", Volume V, Verlag Chemie, 1967, pp. 53 ff., In particular pp. 65 to 69). The acylating agents of the formula IV can be prepared by processes known per se.

When using a carboxylic acid as an acylating agent, it is expedient to add an activating agent which has the task of increasing or activating the acylating potential of the carboxylic acid or the carboxylic acid in situ or preferably shortly before the reaction with the compound of the formula Ia in a reactive carboxylic acid derivative to transfer the formula IV. Suitable activating agents of this type are, for example: N, N'-disubstituted carbodiimides, in particular if they contain at least one secondary or tertiary alkyl radical, such as, for example, diisopropyl, dicyclohexyl or N-methyl-N'-tert.butyl-carbodiimide (cf. Methodicum Chimicum, Verlag G. Thieme, Stuttgart, Vol. 6, (1974), pp. 682/683, and Houben-Weyl, Methods of Org. Chemie, Vol. 8, (1952), pp. 521/522); Carbonic acid derivatives, such as phosgene, chloroformate, in particular with 1 to 5 carbon atoms in the alkyl radical (see, for example, Tetrahedron Letters 24 (1983), 3365 to 3368); Carbonic acid esters, such as N, N'-disuccinimido carbonate, diphthalimido carbonate, 1,1 '- (carbonyldioxy) dibenzotriazole or di-2-pyridyl carbonate (see e.g. Tetrahedron Letters, Vol.25, no. 43, 4943-4946), optionally in the presence of suitable catalysts, such as 4-dimethylaminopyridine. N, N'-carbonyldiazoles, such as N, N'-carbonyldiimidazole, 2,2'-carbonylditriazole (1,2,3), 1,1'-carbonylditriazole (1,2 , 4), N, N'-carbonyl-dipyrazole, 2,2'-carbonyl-ditetrazole, N, N'-carbonyl-benzimidazole or N, N'-carbonyl-benzotriazole, are suitable (cf. for example HA Staab, M. Lücking and FH Dürr, loc.cit; HA Staab and A. Mannschreck loc. Cit .; HA Staab and W. Rohr loc. Cit). The commercial N, N'-carbonyl-diimidazole is often used as the N, N'-carbonyl-diazole. The other N, N'-carbonylazoles are also easily accessible from the respective azole and phosgene.

Also suitable as activating agents for carboxylic acids are: derivatives of oxalic acid, e.g. Oxalyl chloride (see e.g. GB-PS 2 139 225) or N, N'-oxalyl-diazoles such as e.g. 1,1'-oxalyldi-imidazole, 1,1'-oxalyldi-1,2,4-triazole and 1,1'-oxalyldi-1,2,3,4-tetrazole (see e.g. Shizuaka Murata, Bull. Chem Soc. 57: 3597-3598 (1984); Methyl ethylphosphinic anhydride (see e.g. DE-OS 31 01 427); Diphosphorus tetraiodide (Chem. Lett. 1983, 449); Dialkyl disulfite (Indian J. Chem. 21, 259 (1982)); or other reactive agents.

Suitable solvents, dispersants or diluents for the acylation are e.g. those specified for carrying out the cyclization, moreover e.g. Pyridine and amides, e.g. Dimethylformamide. In addition to water, polar organic solvents such as dimethylformamide, dimethyl sulfoxide or pyridine are preferred for the acylation. Mixtures of solvents, e.g. a mixture of water and methylene chloride are suitable.

If a compound of the formula with R ² = -NO is to be prepared, a compound of the formula Ia, which can also be in the form of an acid addition salt, is prepared in a manner known per se, advantageously in a suitable inert solvent or solvent mixture, preferably in water, normally nitrosated at temperatures from 0 to 40 ° C, and preferably at temperatures from 0 to 10 ° C. The nitrosation takes place with nitrous acid, NO, NOCI or NO-containing gas mixtures. The nitrosation is expediently carried out using nitrous acid, which is advantageously produced from an alkali metal nitrite, for example sodium nitrite, and an acid, in particular hydrochloric acid. It is expedient to adjust the aqueous solution of the compound la to an pH of 1 to 3 with an acid, in particular hydrochloric acid, and to add the alkali metal nitrite in the form of an aqueous solution dropwise to the stirred and cooled solution of the compound.

To prepare a compound according to the invention according to process variant b), a 3-aminosydnonimine of the formula III, which can also be in the form of an acid addition salt, is treated with an acid. Catalytic amounts of acid are already sufficient for this treatment. However, a larger molar excess of acid can also be used. Normally the 3-aminosydnonimine of formula 111 or an acid addition salt thereof is contacted with an acid in a molar ratio of 1: (0.1 to 5), preferably 1: (0.1 to, 0.5). This treatment is also advantageously carried out in a suitable organic or inorganic solvent, dispersant or diluent. The reaction temperature is normally 0 ° to the boiling point of the reaction mixture, in particular 0 to 40 ° C, preferably 0 to 20 ° C. To remove the tert-butyl group, a compound of the formula 111 can be left to stand for a long time at room temperature with an acid in a suitable solvent.

Solvents, dispersants or diluents for process variant b) include e.g. those that have been specified for the cyclization according to process variant a).

As acids for the elimination of the tert-butyl group e.g. the acids mentioned in process variant a) as cyclizing agents are used.

In process variant b), acid addition salts of the compounds of the formula Ia are obtained. The compounds of the formula Ia can be converted into other compounds of the formula by the acylation or nitrosation already mentioned.

The substituted 3-amino-sydnonimines of the general formula form acid addition salts with inorganic or organic acids. Inorganic or organic acids are suitable for the formation of such acid addition salts. Suitable acids are, for example, hydrogen chloride, hydrogen bromide, phosphoric, nitric, sulfuric, oxalic, milk, wine, vinegar, salicylic, benzoic, ant, propionic, pivalic, diethylacetic, malonic, Amber, pimeline, fumaric, maleic, apple, sulfamine, phenylpropione, gluconic, ascorbic, isonicotinic, methane sulfonic, p-toluenesulfonic, citric, adipic, naphthalenedisulfonic, especially naphthalenedisulfonic, acids (1, 5). Pharmacologically acceptable acid addition salts are preferred. The acid addition salts can be prepared as usual by combining the components, advantageously in a suitable solvent or diluent.

The acid addition salts are normally obtained in the synthesis of the compounds of the formula Ia.

worin R¹ die bereits genannte Bedeutung besitzt, durch Umsetzung mit Formaldehyd und Blausäure bzw. Natriumcyanid in einem geeigneten Lösungsmittel, z.B. Wasser, hergestellt werden, wobei zunächst eine Verbindung der allgemeinen Formel VI

entsteht, die durch Nitrosierung in die Verbindung II überführt wird. Die Nitrosierung wird in bekannter Weise in einem geeigneten inerten Lösungsmittel oder Lösungsmittelgemisch, vorzugsweise in Wasser, normalerweise bei Temperaturen von 0 bis 40°C, vorzugsweise bei Temperaturen von 0 bis 10°C durchgeführt. Die salpetrige Säure wird dabei normalerweise aus einem Alkalimetallnitrit, z.B. Natriumnitrit, und einer Säure, insbesondere Salzsäure, erzeugt. Es ist zweckmäßig, die wäßrige Lösung der Verbindung VI mit einer Säure, insbesondere Salzsäure auf einen pH-Wert von 1 bis 3 einzustellen und das Alkalimetallnitrit in Form einerwäßrigen Lösung zu der gerührten und abgekühlten Lösung der Verbindung zuzutropfen.The starting compounds of the general formula II required for the synthesis route a) can, provided that R ^{1 is} a bulky radical, such as a secondary or tertiary alkyl group or cycloalkyl, in a manner known per se, according to Strecker's aminonitrile synthesis from hydrazines of the general formula V

wherein R ^{1 has} the meaning already mentioned, by reaction with formaldehyde and hydrocyanic acid or sodium cyanide in a suitable solvent, for example water, are prepared, with a compound of the general formula VI

arises, which is converted into compound II by nitrosation. The nitrosation is carried out in a known manner in a suitable inert solvent or solvent mixture, preferably in water, normally at temperatures from 0 to 40 ° C., preferably at temperatures from 0 to 10 ° C. The nitrous acid is usually generated from an alkali metal nitrite, for example sodium nitrite, and an acid, especially hydrochloric acid. It is advantageous to adjust the aqueous solution of compound VI to an pH of 1 to 3 with an acid, in particular hydrochloric acid, and to add the alkali metal nitrite in the form of an aqueous solution dropwise to the stirred and cooled solution of the compound.

The solution of the compound 11 obtained in this way can be subjected directly to the cyclization reaction. Normally, however, it is appropriate to first take up the nitroso compound II in a suitable organic solvent and, if appropriate after adding a further solvent, to carry out the cyclization to the compound of the formula Ia in it.

The preparation of the starting compounds of the formula V is known or can be carried out by processes known per se.

durch Cyclisierung herstellen, wie dies bei der Verfahrensvariante a) beschrieben worden ist. Da die Cyclisierung durch Einwirkung von Säure durchgeführt wird, tritt bei längerer Säureeinwirkung nach erfolgter Cyclisierung eine Abspaltung der tert.-Butylgruppe ein. Das heißt, daß die Verfahrensvariante b) auch direkt anschließend an die Synthese der Verbindung III durchgeführt werden kann, ohne daß eine Isolierung der Verbindung III erfolgt.The starting compounds of formula III required for process variant b) can be derived from compounds of formula VII

by cyclization, as described for process variant a). Since the cyclization is carried out by the action of acid, the tert-butyl group is split off when the acid has been exposed to the acid for a long time after the cyclization. This means that process variant b) can also be carried out directly after the synthesis of compound III without isolating compound III.

worin R¹ die bereits genannte Bedeutung besitzt, durch Umsetzung mit Formaldehyd und Blausäure bzw. Natriumcyanid in einem geeigneten Lösungsmittel, z.B. Wasser, hergestellt werden, wobei zunächst eine Verbindung der allgemeinen Formel IX

entsteht, die durch Nitrosierung in die Verbindung VII überführt und anschließend cyclisiert wird, wie dies bereits im Zusammenhang mit den Verbindungen der Formel VI bei der Verfahrensvariante a) beschrieben worden ist.The required starting compounds of the general formula VII can be prepared in a manner known per se from Strecker's aminonitrile synthesis from compounds of the general formula VIII

wherein R ^{1 has} the meaning already mentioned, by reaction with formaldehyde and hydrocyanic acid or sodium cyanide in a suitable solvent, for example water, are prepared, with a compound of the general formula IX

arises, which is converted into compound VII by nitrosation and then cyclized, as has already been described in connection with the compounds of formula VI in process variant a).

dadurch herstellen, daß entweder eine Verbindung der Formel X zur N-Nitrosoverbindung XI nitrosiert und anschließend, zweckmäßigerweise mit Lithiumaluminiumhydrid, reduziert wird:

oder daß in an sich bekannter Weise eine Verbindung der Formel X mit Kaliumcyanat im sauren Medium in das HarnstoffderivatXll überführt wird, das dann durch Oxydation mit Natriumhypochlorit nach dem Hoffmann-Abbau in die Verbindung XIII überführt wird.

Some of the compounds of the general formula VIII are known or can be derived from compounds of the general formula X

Prepare by either nitrosating a compound of the formula X to give the N-nitroso compound XI and then reducing it, expediently using lithium aluminum hydride:

or that a compound of the formula X with potassium cyanate is converted in an acidic medium into the urea derivative XII in a manner known per se, which is then converted into the compound XIII by oxidation with sodium hypochlorite after Hoffmann degradation.

The preparation of the starting compounds of the formulas IV and X is known or can be carried out by processes known per se.

The compound of general formula 1 and its pharmacologically acceptable acid addition salts have valuable pharmacological properties. Its effect on the cardiovascular system is particularly pronounced. Compared to known 3-position substituted sydnonimine compounds, e.g. Surprisingly, those of EP-B-59356 and the commercially available structure-like compound molsidomine have a considerably stronger action and a longer duration of action. For example, they lower blood pressure as well as pulmonary artery pressure and left ventricular end-diastolic pressure and thus relieve cardiac activity in the sense of an antianginal effect, without provoking reflex tachycardia.

By inhibiting platelet aggregation, the compounds can also be antithrombotic Show effects.

The compounds of formula 1 and their pharmacologically acceptable acid addition salts can therefore be administered to humans as a remedy on their own, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which, as an active ingredient, have a pharmacologically effective dose of at least one Compound of formula I or an acid addition salt thereof, in addition to conventional pharmaceutically acceptable carriers and additives.

The remedies can be administered orally, e.g. in the form of pills, tablets, lacquered tablets, coated tablets, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures. However, administration can also be rectal, e.g. in the form of suppositories, or parenterally, e.g. in the form of solutions for injection, or percutaneously, e.g. in the form of ointments or tinctures.

Pharmaceutical inert inorganic or organic carriers can be used to produce the pharmaceutical preparations. For the production of pills, tablets, dragees and hard gelatin capsules you can e.g. Use lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. Carriers for soft gelatin capsules and suppositories are e.g. Fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable carriers for the production of solutions and syrups are e.g. Water, sucrose, invert sugar, glucose, polyols etc. For example, suitable carriers for the production of injection solutions are Water, alcohols, glycerin, polyols or vegetable oils.

In addition to the active substances and carriers, the pharmaceutical preparations can also contain additives such as Fillers, extenders, explosives, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colors, flavors or aromatizers, buffer substances, furthermore solvents or solubilizers or agents to achieve a depot effect, as well as salts for changing the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I or their pharmacologically acceptable acid addition salts and still other therapeutically active substances.

Such other therapeutically active substances are, for example: β-receptor blockers, such as e.g. Propranolol, pindolol, metoprolol; Vasodilators, e.g. Carbochromes; Sedatives, e.g. Barbituric acid derivatives, 1,4-benzodiazepines and meprobamate; Diuretics, such as Chlorothiazide; heart tonifying agents such as Digitalis preparations; antihypertensive agents such as Hydralazine, dihydralazine, prazosin, clonidine, Rauwolfia alkaloids; Agents that lower the level of fatty acids in the blood, e.g. Benzafibrate, fenofibrate; Agents for thromboprophylaxis, e.g. Phenprocoumon.

The compounds of the formula I, their pharmacologically acceptable acid addition salts and pharmaceutical preparations which contain the compounds of the formula or their pharmacologically acceptable acid addition salts as active compounds can be used in humans in combating or preventing diseases of the cardiovascular system, for example as antihypertensive medicaments the different forms of high blood pressure, in the fight or prevention of angina pectoris etc. The dosage can vary within wide limits and must be adapted to the individual circumstances in each individual case. In general, a daily dose of about 0.5 to 100 mg, preferably 1 to 20 mg, is appropriate for oral administration per human individual. With other forms of administration, too, the daily dose is, due to the good absorption of the active ingredients, in similar quantity ranges, i.e. generally also at 0.5 to 100 mg / person. The daily dose is usually divided into several, e.g. 2 to 4 sub-administrations divided.

Unless otherwise stated, percentages are given in percentages by weight in the examples below. The stated ratios between components of solvents or flow agents are volume ratios. The statement "Zers." means "decomposition".

Example 1: a) 3- (2-Hydroxyethylamino) -sydnonimine hydrochloride

10 g of 3- (tert-butyl- (2-hydroxyethyl) amino) -sydnonimine hydrochloride are stored in 100 ml of 10% ethanolic hydrochloric acid for 14 days at room temperature (20 ° C). The mixture is stirred in an ice bath for 3 h and the precipitate is filtered off with suction and recrystallized from ethanol. Yield: 5.0 g mp: 145 ° C (dec.)

The 3- (tert-butyl- (2-hydroxyethyl) amino) -sydnonimine hydrochloride required as the starting product is prepared as follows:

b) N-nitroso-tert-butyl- (2-hydroxyethyl) amine

• Ausbeute: 23,9 g Fp. 65-68°C

23.4 g of 2-tert-butylaminoethanol are dissolved in 60 ml of water and 19.7 g of conc. Hydrochloric acid added. The solution of 20.7 g of sodium nitrite in 30 ml of water is added dropwise at 30-40 ° C. When the addition is complete, the mixture is heated to 70 ° C. for an hour and then stirred in an ice bath. The product is filtered off with suction or, in the case of the oily derivatives of the examples below, shaken out with diethyl ether and the ether phase is dried and concentrated.

• Yield: 23.9 g mp 65-68 ° C

c) N-tert-butyl-N- (2-hydroxyethyl) hydrazine

The mixture of 23 g of N-nitroso-tert-butyl- (2-hydroxyethyl) amine and 200 ml of anhydrous tetrahydrofuran is mixed in portions at 60 ° C. with a total of 12.2 g of lithium alanate. When the addition is complete, the mixture is heated to 60 ° C. for 1 hour, cooled in an ice bath and the excess lithium alanate is hydrolyzed by carefully adding methanol and then water. The solids are removed by suction and the filtrate is concentrated. A colorless oil (14 g) remains, which can be used without further purification.

d) 3- (tert-Butyl- (2-hydroxyethyl) amino) -sydnonimine hydrochloride

• Ausbeute: 5,9 g Fp = 161-163°C (Zers.)

The oil obtained in step c (14 g) is concentrated in 50 ml of water and 8.1 g. Hydrochloric acid dissolved and cooled to -5 ° C. Then the solution of 6.6 g of potassium cyanide in 20 ml of water is added dropwise. After adding 15 ml of ethanol, a 39% formalin solution (8.2 g) is added dropwise and the pH of the mixture is adjusted to 7. It is stirred for 2 hours at room temperature, with conc. Hydrochloric acid adjusted to pH = 1.5 and the solution of 5.6 g of sodium nitrite in 25 ml of water was added dropwise while cooling with ice. It is stirred overnight at room temperature and then extracted with diethyl ether, dried and concentrated. The remaining oil is concentrated in 50 ml. dissolved methanolic hydrochloric acid and diluted with 50 ml of ethyl acetate. The precipitate is filtered off and discarded. The filtrate is concentrated after 2 hours and the residue is stirred with ethyl acetate and the solid is filtered off with suction and recrystallized from ethanol / diethyl ether (1: 2).

• Yield: 5.9 g mp = 161-163 ° C (dec.)

Example 2: 3-ethylamino-sydnonimine hydrochloride

• Ausbeute: 4,4 g Fp.: 177°C (Zers.)

The solution of 26.55 g of N-tert-butyl-N-ethyl-hydrazine hydrochloride and of 9.38 g of sodium cyanide in 100 ml of water is mixed at 0 to 5 ° C. with 14.5 g of 39% formalin. This mixture is stirred for 16 h at room temperature, the pH being adjusted to 7-7.5. The pH is then adjusted to 1.0 by adding concentrated hydrochloric acid, the mixture is cooled in an ice bath and a solution of 9.5 g of sodium nitrite in 20 ml of water is added dropwise. The resulting nitroso compound is extracted with ether, dried and concentrated. The remaining oil is mixed with 10 ml of isopropanol and mixed with hydrogen chloride dissolved in ethyl acetate and kept at room temperature for one day. The formation of the precipitate is increased by cooling to 0 ° C. and the precipitate is suctioned off and recrystallized from isopropanol.

• Yield: 4.4 g mp: 177 ° C (dec.)

Example 3: N-ethoxycarbonyl-3-ethylamino-sydnonimine

• Ausbeute: 4,6 g Fp.: 131 °C (Zers.)

The solution, cooled to 0 ° C., of 7.9 g of 3-ethylamino-sydnonimine hydrochloride in 30 ml of water is mixed with 7.5 g of sodium bicarbonate and then with a solution of 5.8 g of ethyl chloroformate in 30 ml of methylene chloride and added for 15 hours Room temperature stirred. The methylene chloride phase is separated off, dried and concentrated. The remaining oil is purified by column chromatography (silica gel; CH ₂ Cl ₂ : MeOH = 98: 2) and crystallized by stirring with diisopropyl ether.

• Yield: 4.6 g mp: 131 ° C (dec.)

Example 4: 3-cyclohexylamino-sydnonimine hydrochloride a) N-nitroso-tert-butyl-cyclohexyl-amine

• Ausbeute: 16,3 g Fp.: 87°C

The mixture consisting of 13.2 ml of 10N hydrochloric acid, 50 ml of water, 18.8 g of tert-butylcyclohexylamine and 17.9 g of sodium nitrite is heated to 90 ° C. for 3 hours. A solid precipitates on cooling and is suctioned off.

• Yield: 16.3 g mp: 87 ° C

b) N-tert-butyl-N-cydohexyl hydrazine hydrochloride

The mixture of 50 ml of tetrahydrofuran, 100 ml of dibutyl ether, 0.38 g of lithium alanate and 1.8 g of nitroso-tert-butyl-cyclohexylamine is heated to boiling under nitrogen for 2 hours. Then 14.5 g of nitroso compound are added all at once and a total of 3.8 g of lithium alanate in 3 portions within 5 hours, and the mixture is heated to 90 ° C. during this time. After the reaction has ended, the remaining lithium alanate is destroyed by carefully adding dropwise water with cooling, the solid which forms is filtered off with suction and the filtrate is shaken out with 2 portions of 1N hydrochloric acid (100 ml each). The aqueous phase, which contains the hydrazine hydrochloride, is shaken out with ether and used for the next step without further purification.

c) N-tert-butyl-N-cyclohexyl-N'-cyanomethyl hydrazine

• Ausbeute: 12,2 g

The solution of hydrazine hydrochloride obtained under b is stirred in an ice bath and 4 g of sodium cyanide are added. The mixture is neutralized and 7.7 g of a 39% formalin solution are added dropwise. The pH is adjusted to 7 by adding sodium carbonate solution, the mixture is stirred at room temperature for 2 hours and the product is extracted with diethyl ether. After drying and concentration, a yellow oil remains, which is used for the next step without further cleaning.

• Yield: 12.2 g

d) 3- (tert-Butyl-cyclohexyl-amino) -sydnonimine hydrochloride

• Ausbeute: 6,7 g Fp.: 158°C (Zers.)

The oil obtained under c is dissolved in 100 ml of water and mixed with 6 ml of 10N HCl. Then the solution of 6.9 g of sodium nitrite in 20 ml of water is added dropwise and the mixture is stirred for one hour at room temperature. The nitroso intermediate is shaken out with ethyl acetate (50 ml), the ethyl acetate phase is dried and treated with excess ethereal hydrochloric acid at 0-5 ° C. The oil which separates out is purified by column chromatography (silica gel, MeOH: CH ₂ C1 ₂ = 1: 9). After the appropriate fractions have been concentrated in a rotary evaporator, the residue is stirred with diethyl ether and the solid is filtered off with suction.

• Yield: 6.7 g mp: 158 ° C (dec.)

e) 3-Cyclohexylamino-sydnonimine hydrochloride

• Ausbeute: 2,5 g Fp.: 90°C (Zers.)

The solution of 4 g of 3- (tert-butyl-N-cyclohexyl-amino) -sydnonimine hydrochloride in 30 ml of conc. ethanolic hydrochloric acid is left to stand at room temperature for one day and then concentrated on a rotary evaporator. The residue is purified by column chromatography (silica gel, CH ₂ Cl ₂ : MeOH = 9: 1) and the residue obtained after concentrating the corresponding fractions is stirred with isopropyl acetate and suction filtered.

• Yield: 2.5 g mp: 90 ° C (dec.)

Example 5 3- (2-Hydroxycylohexyl-amino) -sydnonimine hydrochloride a) N-tert-Butyl-N- (2-hydroxycylohexyl) hydrazine hydrochloride

• Ausbeute: 28,5 g Fp.: 145°C (Zers.)

To dissolve 38.8 g of N-nitroso-tert-butyl- (2-hydroxycyclohexyl) -amine (obtained by heating 1,2-epoxycyclohexane with tert-butylamine to 150 ° C in an autoclave and then nitrosing with sodium nitrite / HCl) 10 g of lithium alanate are added in portions of 1 g within 2 days under a nitrogen atmosphere, the mixture being heated to 50.degree. The remaining lithium alanate is by cooling the Mix and carefully dropwise drop 50 ml of methanol and then 75 ml of water destroyed. The mixture is then filtered and the filtrate is concentrated. The residue is taken up in 100 ml of methylene chloride, the water which separates off and the organic phase is dried and concentrated again. The oil thus obtained is dissolved in 20 ml of ethanol and 150 ml of tert-butyl methyl ether and the hydrazine hydrochloride is precipitated by adding ethereal HCl.

• Yield: 28.5 g mp: 145 ° C (dec.)

b) 3- (2-Hydroxycylohexylamino) -sydnonimine hydrochloride

• Ausbeute: 4,5 g Fp.: 174-5°C (Zers.)

The mixture of 13.35 g of N-tert-butyl-N- (2-hydroxycylohexyl) hydrazine hydrochloride, 3.1 g of sodium cyanide and 50 ml of water is stirred in an ice bath and added dropwise with a 39% formalin solution (5, 7 g) added. The pH of the mixture is adjusted to 7 to 7.5 and stirred for 3 hours at room temperature. Then with conc. Hydrochloric acid to pH = 1 and the solution of 6 g of sodium nitrite in 25 ml of water was added dropwise. After one hour, the nitroso compound is extracted with diethyl ether, the ethereal phase is dried and ethereal HCl is added. After 2 days, the precipitate is filtered off and recrystallized from isopropanol / ethyl acetate.

• Yield: 4.5 g mp: 174-5 ° C (dec.)

Example 6 N-benzoyl-3- (2-hydroxycylohexylamino-sydnonimine

• Ausbeute: 1,6 g Fp.: 174°C (Zers.)

The solution, cooled to 5 ° C., of 1.9 g of 3- (2-hydroxycylohexylamino) -sydnonimine hydrochloride and 1.7 g of sodium bicarbonate in 20 ml of water is mixed with the solution of 1.45 g of benzoyl chloride in 20 ml of methylene chloride and stirred for 4 hours in an ice bath. The precipitate is filtered off and recrystallized from isopropanol.

• Yield: 1.6 g mp: 174 ° C (dec.)

Example 7 N-Cyclohexylcarbonyl-3- (2-hydroxycylohexylamino) -sydnonime

The cooled to 5 ° C solution of 3.5 g of 3- (2-hydroxycyclohexyl-amino) -sydnonimine hydrochloride and 2.6 g of sodium bicarbonate in 30 ml of water is chloride with the solution of 3.3 g of cyclohexane carboxylic acid chloride in 30 ml of methylene added and stirred for 20 hours at room temperature. The methylene chloride phase is separated off, dried and concentrated. The residue is recrystallized from isopropyl acetate. Yield: 2.6 g mp: 155 ° C (dec.)

Example 8 N- (4-chlorobenzoyl-3- (2-hydroxycylohexylamino) -sydnonime

• Ausbeute: 3,3 g Fp.: 169°C (Zers.)

The solution of 3.5 g of 3- (2-hydroxycylohexylamino) -sydnonim hydrochloride in 30 ml of water is cooled to 5 ° C. and successively with 2.6 g of sodium carbonate and the solution of 3.9 g of 4-chlorobenzoyl chloride in 30 ml of methylene chloride are added and the mixture is stirred at room temperature for 20 hours. The organic phase is separated off, dried and concentrated. The oily residue is crystallized from di-n-propyl ether.

• Yield: 3.3 g mp: 169 ° C (dec.)

Example 9 N-ethoxycarbonyl-3- (2-hydroxycylohexylamino-sydnonim

• Ausbeute: 5,8 g Fp.: 147°C

This compound is prepared analogously to Example 8 from 7.6 g of 3- (2-hydroxycylohexylamino) -sydnonim hydrochloride, 3.4 g of ethyl chloroformate and 5.5 g of sodium bicarbonate and recrystallized from isopropyl acetate.

• Yield: 5.8 g mp: 147 ° C

The following examples A to F relate to pharmaceutical preparations.

Example A

Example B

Example C

Example D

Example E

Example F

Die pharmakologische Wirkung der Verbindung der Formel wurde nach einer modifizierten Methode von Godfraind and Kaba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl) 35 bis 49, 1972) und von Schümann et al (Naunyn-Schmiedeberg's Arch. Pharmacol. 289, 409 bis 418, 1975) ermittelt. Dabei werden Spiralstreifen der Arteria pulmonalis des Meerschweinchens nach Äquilibrierung in calciumfreier Tyrodelösung mit 40 mmol/l Kalium depolarisiert. Ein Zusatz von 0,5 mmol/l CaCI2löst dann eine Kontraktion aus. Die relaxierende Wirkung der Prüfsubstanz wird durch kumulative Zugabe von in 1/2 log 10 ab gestuften Konzentrationen ermittelt. Aus der Konzentrationswirkungskurve (Abszisse: -log mol/l Prüfsubstanz, Ordinate: % Hemmung der maximalen Kontraktion, Mittelwert von 4 bis 6 Gefäßstreifen) wird die Konzentration der Prüfsubstanz ermittelt, welche die Kontraktion um 50% hemmt (= IC₅₀, mol/I). In der folgenden Tabelle sind die so erhaltenen IC₅₀-Werte angegeben. Wie der Vergleich mit dem IC₅₀-Werte:> 1·10^-4 für die bekannte Verbindung Molsidomin (N-Ethoxycarbonyl-3-morpholino-sydnonimin), vgl. DE-B-16 95 897, ergibt, liegen die Werte für die Verbindungen der Formel I erheblich günstiger.

The pharmacological activity of the compound of the formula was determined using a modified method from Godfraind and Kaba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl) 35 to 49, 1972) and from Schümann et al (Naunyn-Schmiedeberg's Arch. Pharmacol. 289 , 409 to 418, 1975). Spiral strips of the pulmonary artery of the guinea pig are depolarized with 40 mmol / l potassium after equilibration in calcium-free Tyrode solution. An addition of 0.5 mmol / l CaCl2 then triggers a contraction. The relaxing effect of the test substance is determined by the cumulative addition of concentrations graded in 1/2 log 10. From the concentration effect curve (abscissa: -log mol / l test substance, ordinate:% inhibition of maximum contraction, mean value of 4 to 6 vascular strips), the concentration of the test substance is determined, which inhibits the contraction by 50% (= IC ₅₀ , mol / I ). The IC ₅₀ values thus obtained are given in the following table. As the comparison with the IC ₅₀ values:> 1 · 10 ^-4 for the known compound molsidomine (N-ethoxycarbonyl-3-morpholino-sydnonimine), cf. DE-B-16 95 897, the values for the compounds of the formula I are considerably more favorable.

Claims (11)

1. Pharmacologically active substituted 3-aminosydnonimines of the general formula I

and their pharmacologically acceptable acid addition salts, wherein

R¹ denotes alkyl having 1 to 8 C atoms, cycloalkyl having 5 to 8 C atoms, it also being possible for the alkyl or cycloalkyl radical to be substituted by -OR⁴ or -N(R⁵, R⁶), or adamantyl,

R² denotes hydrogen, -NO or the radical -COR³,

R³ denotes an aliphatic radical having 1 to 6 C atoms, which can also be substituted by alkoxy having 1 to 6 C atoms or by an alkyl thio radical having up to 4 C atoms or by allylthio; a cycloaliphatic radical having 5 to 7 C atoms; a bicycloaliphatic radical having 7 to 14 C atoms; a tricycloaliphatic radical having 7 to 16 C atoms; an alkoxy radical having 1 to 6 C atoms, which can also be substituted by alkoxy having 1 to 6 C atoms; an aryloxy radical having 6 to 10 C atoms; an alkoxycarbonyl radical having a total of 2 to 7 C atoms; an aryl radical having 6 to 10 C atoms; an aryl radical having 6 to 10 C atoms which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 3 C atoms and/or 1 to 3 alkoxy radicals having 1 to 3 C atoms and/or 1 or 2 nitro groups and/or 1 or 2 hydroxyl groups and/or 1 or 2 alkylcarbonyloxy radicals having 1 to 4 C atoms in the alkyl portion; or imidazolyl and

R⁴, R⁵, R⁶ denote hydrogen or alkyl having 1 to 6 C atoms.

2. Substituted 3-aminosydnonimines according to Claim 1, characterized in that R¹ denotes alkyl having 1 to 6 C atoms, hydroxyalkyl having 2 to 6 C atoms, cyclohexyl, hydroxycyclohexyl or adamantyl.

3. Substituted 3-aminosydnonimines according to Claim 1 and/or 2, characterized in that R² denotes hydrogen, acetyl, propionyl, i-propylcarbonyl, tert.-butylcarbonyl, cyclohexylcarbonyl, benzoyl, 4-chlorobenzoyl, methoxycarbonyl, ethoxycarbonyl, i-propoxycarbonyl, butoxycarbonyl or allylthiomethylcarbonyl.

4. 3-Cyclohexylamino-sydnonimine and its pharmacologically acceptable acid addition salts, in particular its hydrochloride.

5. 3-(Adamant-1-yl)-amino-sydnonimine and its pharmacologically acceptable acid addition salts, in particular its hydrochloride.

6. 3-(2-Hydroxycyclohexyl)-amino-sydnonimine and its pharmacologically acceptable acid addition salts, in particular its hydrochloride.

7. Process for the preparation of the compounds of the formula I mentioned in one or more of Claims 1 to 3 or of the compounds mentioned in Claims 4 to 6, characterized in that

a) a compound of the general formula II

wherein R¹ has the meaning already given, is cyclized to give a compound of the general formula la

and in that this compound or an acid addition salt thereof, in the case where a compound of the formula I where R² = -COR³ is to be prepared, is acylated with an acylating agent which introduces the radical -COR³, or, in the case where a compound of the formula I where R² = -NO is to be prepared, is nitrosated, and if appropriate the compound thus obtained is converted into a pharmacologically acceptable acid addition salt, or in that

b) the tert.-butyl radical is split off from a 3-aminosydnonimine of the formula III

wherein R¹ and R² have the meanings already given, which can also be in the form of an acid addition salt, and is replaced by hydrogen, a compound of the formula la initially being formed, and in that, in the case where a compound of the formula I where R² = -COR³ is prepared, the compound of the formula la or an acid addition salt thereof is acylated with an acylating agent which introduces the radical -COR³, or in the case where a compound of the formula I where R² = -NO is to be prepared, is nitrosated, and if appropriate the resulting compound is converted into a pharmacologically acceptable acid addition salt.

8. Process according to Claim 7, characterized in that the cyclization or splitting off of the tert.-butyl radical is carried out in a solvent, dispersing agent or diluent at temperatures of 0 to 40°C, preferably 0 to 20°C, with the aid of an acid which establishes a pH of 3 or less in aqueous solution.

9. Substituted 3-aminosydnonimines of claims 1 to 6 or their pharmacologically acceptable acid addition salts as pharmacological active compounds for use in combating and preventing cardiovascular diseases.

10. Pharmaceutical preparation, characterized in that it contains a compound of Claims 1 to 6 or a pharmacologically acceptable acid addition salt thereof as the active compound, together with pharmaceutically acceptable excipients and additives and if appropriate also one or more other pharmacological active compounds.

11. Substituted 3-aminosydnonimines of the general formula III

and their acid addition salts, wherein

R¹ denotes alkyl having 1 to 8 C atoms, cycloalkyl having 5 to 8 C atoms, it also being possible for the cycloalkyl or an alkyl radical having 4 to 8 C atoms to be substituted by -OR⁴ or -N(R⁵, R⁶), or adamantyl, R² denotes hydrogen, -NO or the radical -COR³,

R³ denotes an aliphatic radical having 1 to 6 C atoms, which can also be substituted by alkoxy having 1 to 6 C atoms or by an alkyl thio radical having up to 4 C atoms or by allylthio; a cycloaliphatic radical having 5 to 7 C atoms; a bicycloaliphatic radical having 7 to 14 C atoms; a tricycloaliphatic radical having 7 to 16 C atoms; an alkoxy radical having 1 to 6 C atoms, which can also be substituted by alkoxy having 1 to 6 C atoms; an aryloxy radical having 6 to 10 C atoms; an alkoxycarbonyl radical having a total of 2 to 7 C atoms; an aryl radical having 6 to 10 C atoms; an aryl radical having 6 to 10 C atoms which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 3 C atoms and/or 1 to 3 alkoxy radicals having 1 to 3 C atoms and/or 1 or 2 nitro groups and/or 1 or 2 hydroxyl groups and/or 1 or 2 alkylcarbonyloxy radicals having 1 to 4 C atoms in the alkyl portion; or imidazolyl and

R⁴, R⁵, R⁶ denote hydrogen or alkyl having 1 to 6 C atoms.